Neurodegenerative diseases (NDs) are a large group of pathologies caused by metabolic changes in brain cells, loss of synapses and other compartments of neurons, and finally neuronal death (Neurodegenerative diseases: From Molecular Concepts to Therapeutic Targets. Editors: R. von Bernhardi, N. C. Inestrosa, Nova Publishers, 2008; Neurodegenerative diseases: Clinical aspects, Molecular Genetics and Biomarkers. Editors: D. Galimberti, E. Scarpini, Springer, 2014). This group of diseases includes Mild Cognitive Impairment (MCI), Alzheimer's disease (AD), Lewy Body dementia, Parkinson's disease (PD), Huntington's disease (HD), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), vascular dementia, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), prion diseases, different ataxias, and others. Due to the increased lifespan, NDs become very common in developed countries. There are about 65 million people living with AD and PD, respectively, and in the U.S. alone, 70-80 million people are at risk of developing one of these conditions.
NDs, and AD specifically, are characterized by neuronal death in different disease-specific areas of the brain. The accumulation of proteinaceous amyloid fiber plaques in the central nervous system initiates and regulates the pathogenic cascade of AD (Hardy, J.; Selkoe, D. J. Science 2002, 297, 353-356; Hardy, J. A.; Higgins, G. A. Science 1992, 256, 184-185). A central event associated with the progression of AD is the oligomerization and subsequent aggregation of amyloid beta (Abeta or Aβ) peptide and its subsequent conversion into β-sheet rich fibers en route to the formation of amyloid plaques (Haass, C.; Selkoe, D. J. Nat. Rev. Mol. Cell Biol. 2007, 8, 101-112).
Aβ is derived from the transmembrane portion of the secreted protein, amyloid precursor protein (APP). Cleavage of APP results in several Aβ isoforms. The predominant species are Aβ42 and Aβ40. The longer variant of Aβ, Aβ42 is the main constituent of amyloid plaques and is far more neurotoxic than Aβ40 (Iwatsubo, T.; Odaka, A.; Suzuki, N.; Mizusawa, H.; Nukina, N.; Ihara, Y. Neuron 1994, 13, 45-53). Previously, according to the amyloid cascade hypothesis, it was believed that plaques resulting from β-sheet formation are responsible for AD onset. However, in recent years, it has been established that the prefibrillar soluble oligomers of Aβ, and not the fibers themselves, are the key neurotoxic species. The accumulation of these oligomeric intermediates leads to presynaptic loss and eventual neuronal cell death. The implication of Aβ oligomeric intermediates in cellular dysfunction and AD make them an important target for therapeutic intervention. However, the dearth of structural information about the soluble oligomers of Aβ presents a challenging task in identifying suitable strategies to modulate Aβ structure and function.
Aβ40 and Aβ42 exist predominantly as random coils in aqueous solution, and are known to sample a range of secondary structures under specific conditions (Riek, R.; Güntert, P.; Döbeli, H.; Wipf, B.; Wüthrich, K. Eur. J. Biochem. 2001, 268, 5930-5936). Under matched conditions, the aggregation of Aβ42 is more aggressive than Aβ40 (Yan, Y.; Wang, C. J. Mol. Biol. 2006, 364, 853-862). The secondary structures of both peptides are almost identical except that Aβ42 adopts a more rigid structure at its C-terminus. In the presence of sodium dodecyl sulfate (SDS) micelles and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), both peptides adopt α-helical conformations from residues 15-24 and 29-35 with residues 16, 20, 22, and 23 exposed to solvent (Jarvet, J.; Danielsson, J.; Damberg, P.; Oleszczuk, M.; GrÃslund, A. J. Biomol. NMR 2007, 39, 63-72; Coles, M.; Bicknell, W.; Watson, A. A.; Fairlie, D. P.; Craik, D. J. Biochemistry 1998, 37, 11064-11077; Serpell, L. C. Biochim. Biophys. Acta 2000, 1502, 16-30).
Numerous small molecules have been identified that modulate the kinetic pathways of Aβ oligomerization. These molecules were principally discovered via high throughput screening (HTS), rational design based on the β-sheet structure of Aβ, and mimicry of short Aβ segments. Some effective modulators of Aβ assembly include the polyphenols (−) epigallocatechin-3-gallate (EGCG) and resveratrol, the sugar derivative scyllo-inositol, molecular tweezers (MTs), Methylene Blue, ligand D-737 and its analogs, cucurbit[7]uril, β-cyclodextrins, cyclic D,L-α-peptides, a C-terminal Aβ peptide fragment, cyclic-KLVFF (D and L) and its analogues, congo red, curcumin, trimeric aminopyrazole carboxylic acid derivatives, affibody proteins, and peptoids. (Ehrnhoefer, D. E.; Bieschke, J.; Boeddrich, A.; Herbst, M.; Masino, L.; Lurz, R.; Engemann, S.; Pastore, A.; Wanker, E. E. Nat Struct Mot Blot 2008, 15, 558-566; Palhano, F. L.; Lee, J.; Grimster, N. P.; Kelly, J. W. J. Am. Chem. Soc. 2013, 135, 7503-7510; Ladiwala, A. R. A.; Lin, J. C.; Bale, S. S.; Marcelino-Cruz, A. M.; Bhattacharya, M.; Dordick, J. S.; Tessier, P. M. J. Biol. Chem. 2010, 285, 24228-24237; McLaurin, J.; Golomb, R.; Jurewicz, A.; Antel, J. P.; Fraser, P. E. J. Biol. Chem. 2000, 275, 18495-18502; Sinha, S.; Lopes, D. H. J.; Du, Z.; Pang, E. S.; Shanmugam, A.; Lomakin, A.; Talbiersky, P.; Tennstaedt, A.; McDaniel, K.; Bakshi, R.; Kuo, P.; Ehrmann, M.; Benedek, G. B.; Loo, J. A.; KlÃrner, F.; Schrader, T.; Wang, C.; Bitan, G. J. Am. Chem. Soc. 2011, 133, 16958-16969; Necula, M.; Breydo, L.; Milton, S.; Kayed, R.; van, d. V.; Tone, P.; Glabe, C. G. Biochemistry 2007, 46, 8850-8860; McKoy, A. F.; Chen, J.; Schupbach, T.; Hecht, M. H. Chem. Biol. Drug Des. 2014, 84, 505-512; McKoy, A. F.; Chen, J.; Schupbach, T.; Hecht, M. H. J. Biol. Chem. 2012, 287, 38992-39000; Lee, H. H.; Choi, T. S.; Lee, S. J. C.; Lee, J. W.; Park, J.; Ko, Y. H.; Kim, W. J.; Kim, K.; Kim, H. I. Angew. Chem. Int. Ed. 2014, 53, 7461-7465; WahlstrÃm, A.; Cukalevski, R.; Danielsson, J.; Jarvet, J.; Onagi, H.; Rebek, J.; Linse, S.; GrÃslund, A. Biochemistry 2012, 51, 4280-4289; Richman, M.; Wilk, S.; Chemerovski, M.; WÃrmlÃnder, Sebastian K. T. S.; WahlstrÃm, A.; GrÃslund, A.; Rahimipour, S. J. Am. Chem. Soc. 2013, 135, 3474-348; Fradinger, E. A.; Monien, B. H.; Urbanc, B.; Lomakin, A.; Tan, M.; Li, H.; Spring, S. M.; Condron, M. M.; Cruz, L.; Xie, C.; Benedek, G. B.; Bitan, G. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 14175-14180; Arai, T.; Araya, T.; Sasaki, D.; Taniguchi, A.; Sato, T.; Sohma, Y.; Kanai, M. Angew. Chem. Int. Ed. 2014, 53, 8236-8239; Arai, T.; Sasaki, D.; Araya, T.; Sato, T.; Sohma, Y.; Kanai, M. ChemBioChem 2014, 15, 2577-2583; Yang, F.; Lim, G. P.; Begum, A. N.; Ubeda, O. J.; Simmons, M. R.; Ambegaokar, S. S.; Chen, P. P.; Kayed, R.; Glabe, C. G.; Frautschy, S. A.; Cole, G. M. J. Biol. Chem. 2005, 280, 5892-5901; HochdÃrffer, K.; MÃrz-Berberich, J.; Nagel-Steger, L.; Epple, M.; Meyer-Zaika, W.; Horn, A. H. C.; Sticht, H.; Sinha, S.; Bitan, G.; Schrader, T. J. Am. Chem. Soc. 2011, 133, 4348-4358).
Some Aβ modulators act as ligands to induce or stabilize a secondary structure in Aβ, and thus alter its function. For example, a peptoid and an affibody protein were shown to trap Aβ into the central discordant α-helical structure and a β-hairpin conformation, reminiscent of membrane-bound Aβ and Aβ fibril structure, respectively. The interaction of the peptoid with Aβ induced an α-helical structure, which altered the aggregation kinetics of Aβ and rescued PC12 cells from cytotoxicity mediated by Aβ. (See Nerelius, C.; Sandegren, A.; Sargsyan, H.; Raunak, R.; Leijonmarck, H.; Chatterjee, U.; Fisahn, A.; Imarisio, S.; Lomas, D. A.; Crowther, D. C.; Stromberg, R.; Johansson, J. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 9191-9196 and Hoyer, W.; Grönwall, C.; Jonsson, A.; Ståhl, S.; Härd, T. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 5099-5104, respectively). Despite these advances in the art, to date, there is no cure or effective therapy for reducing a patient's amyloid burden or preventing amyloid deposition in AD and other amyloid diseases.
Alphα-helical mimetics are organic scaffolds that imitate the topography of an α-helix, such as those present at protein-protein interfaces. On a molecular level, the surface functionalities of α-helical mimetics are spatially oriented in a well-defined order to mimic the side chain residues of one helical surface at positions i, i+3/i+4, and i+7. α-helical mimetics have previously been shown to act as antagonists of numerous protein-protein interactions, including HIV gp41 oligomerization, Bak BH3/Bcl-xL, p53/HDM2, HIF1α/p300, and membrane-bound α-helical intermediates of islet amyloid polypeptide (IAPP) (Saraogi, I.; Hebda, J.; Becerril, J.; Estroff, L.; Miranker, A.; Hamilton, A. Angew. Chem. Int. Ed. 2010, 49, 736-739; Kulikov, O. V.; Kumar, S.; Magzoub, M.; Knipe, P. C.; Saraogi, I.; Thompson, S.; Miranker, A. D.; Hamilton, A. D. Tet. Lett. 2015, 56, 3670-3673; Kumar, S.; Birol, M.; Miranker, A. D. Chem. Comm. 2016, 52, 6391-6394).
Previously, certain oligopyridylamide-based α-helical mimetics have been used to target the membrane-associated α-helical conformation of IAPP and were found to be strong antagonists of membrane-catalyzed IAPP aggregation. Structure-activity relationship studies were conducted to optimize the inhibitory activity against IAPP self-assembly via charge complementarity and hydrophobic interactions. In addition to in vitro solution biophysical assays confirming the inhibition of self assembly, these α-helical mimetics were shown to be effective in rescuing an insulin secreting cell line from IAPP-mediated cytotoxicity. (Kumar, S.; Schlamadinger, D.; Brown, M.; Dunn, J.; Mercado, B.; Hebda, J.; Saraogi, I.; Rhoades, E.; Hamilton, A.; Miranker, A. Chem. Biol. 2015, 22, 369-378; Hebda, J. A.; Saraogi, I.; Magzoub, M.; Hamilton, A. D.; Miranker, A. D. Chem. Biol. 2009, 16, 943-950).
IAPP and Aβ share ˜50% sequence similarity, with the Aβ(15-21) and Aβ(26-32) sequences sharing particular commonality with those of IAPP(10-16) and IAPP(21-27), respectively. These regions are further thought to participate in amyloidogenesis. These similarities likely account for the observation that many Aβ antagonists also inhibit IAPP amyloid formation and vice versa. Yet, despite certain similarities, IAPP and Aβ are implicated in vastly different diseases and conditions. Accordingly, there exists a need in the art for developing compounds that would exhibit specificity and/or selectivity for Aβ versus IAPP,
As discussed herein, several disease-specific amyloidogenic proteins share similar structural and functional properties. These proteins are believed to proceed through a series of conformation switches starting from the native disordered state to soluble oligomeric intermediates which eventually terminate into highly ordered intractable fiber aggregates. An increasing body of evidence suggests that soluble oligomers of the amyloidogenic proteins are the predominant cytotoxic species associated with various amyloid-related diseases. Therefore, elucidation of the structural details of these oligomeric intermediates may provide mechanistic insight for the development of effective therapeutics. Enormous efforts have been directed to identify and characterize these oligomers with limited success because of their complex and dynamic nature. Study of Aβ oligomerization processes by Teplow et al suggested two strategies that could fit the portrait of an ideal therapeutic agent (Ono, K.; Condron, M. M.; Teplow, D. B. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 14745-14750). (1) Conformational organization of the native monomeric state of Aβ which could potentially alter the oligomerization and other downstream functions of Aβ. (2) Destabilization of the oligomeric states to block further oligomerization and fibril formation.
The foregoing discussion is presented solely to provide a better understanding of nature of the problems confronting the art and should not be construed in any way as an admission as to prior art nor should the citation of any reference herein be construed as an admission that such reference constitutes “prior art” to the instant application.